miR-125b-5p delivered by adipose-derived stem cell exosomes alleviates hypertrophic scarring by suppressing Smad2.

Background: Hypertrophic scarring is the most serious and unmet challenge following burn and trauma injury and often leads to pain, itching and even loss of function. However, the demand for ideal scar prevention and treatment is difficult to satisfy. We aimed to discover the effects and mechanisms of adipose-derived stem cell (ADSC) exosomes in hypertrophic scarring. Methods: ADSC exosomes were isolated from the culture supernatant of ADSCs and identified by nanoparticle tracking analysis, transmission electron microscopy and western blotting. The effect of ADSC exosomes on wound healing and scar formation was detected by the wound model of BALB/c mice. We isolated myofibroblasts from hypertrophic scar tissue and detected the cell viability, proliferation and migration of myofibroblasts. In addition, collagen formation and fibrosis-related molecules were also detected. To further disclose the mechanism of ADSC exosomes on fibrosis in myofibroblasts, we detected the expression of Smad2 in hypertrophic scar tissue and normal skin and the regulatory mechanism of ADSC exosomes on Smad2. Injection of bleomycin was performed in male BALB/c mice to establish an in vivo fibrosis model while ADSC exosomes were administered to observe their protective effect. The tissue injury of mice was observed via hematoxylin and eosin and Masson staining and related testing. Results: In this study, we found that ADSC exosomes could not only speed up wound healing and improve healing quality but also prevent scar formation. ADSC exosomes inhibited expression of fibrosis-related molecules such as α-smooth muscle actin, collagen I (COL1) and COL3 and inhibited the transdifferentiation of myofibroblasts. In addition, we verified that Smad2 is highly expressed in both hypertrophic scar tissue and hypertrophic fibroblasts, while ADSC exosomes downregulated the expression of Smad2 in hypertrophic fibroblasts. Further regulatory mechanism analysis revealed that microRNA-125b-5p (miR-125b-5p) is highly expressed in ADSC exosomes and binds to the 3' untranslated region of Smad2, thus inhibiting its expression. In vivo experiments also revealed that ADSC exosomes could alleviate bleomycin-induced skin fibrosis and downregulate the expression of Smad2. Conclusions: We found that ADSC exosomes could alleviate hypertrophic scars via the suppression of Smad2 by the specific delivery of miR-125b-5p.

PTEN hinders the formation of scars by regulating the levels of proteins in the extracellular matrix and promoting the apoptosis of dermal fibroblasts through Bcl-xL.

Hypertrophic scar (HS) is a dermatological condition characterized by an excessive accumulation of proteins in the extracellular matrix (ECM) and an elevated cell count. The development of HS is thought to be linked to the disruption of dermal fibroblast proliferation and apoptosis. The processes of cell proliferation and apoptosis are notably influenced by PTEN. However, the precise mechanisms by which PTEN regulates hypertrophic scar fibroblasts (HSFs) and its overall role in scar formation are still not fully understood. The objective of this study was to investigate the influence of PTEN on hypertrophic scars(HS) and its function in the regulation of scar formation, with the aim of identifying a pivotal molecular target for scar treatment. Our results demonstrate that the overexpression of PTEN (AdPTEN) significantly suppressed the expression of type I collagen (Col I), type III collagen (Col III), and alpha smooth muscle actin (α-SMA) in HSFs. Furthermore, it was observed that the introduction of AdPTEN resulted in the suppression of Bcl-xL expression, which consequently led to an increase in the apoptosis of HSFs. Similarly, in the inhibition of collagens expression and subsequent increase in HSF apoptosis were also observed upon silencing Bcl-xL (sibcl-xL). Additionally, the in vitro model demonstrated that both AdPTEN and sibcl-xL were effective in reducing the contraction of FPCL. The findings of our study provide validation for the role of PTEN in inhibiting the development of hypertrophic scars (HS) by modulating the expression of extracellular matrix (ECM) proteins and promoting apoptosis in hypertrophic scar fibroblasts (HSFs) via Bcl-xL. These results indicate that PTEN and Bcl-xL may hold promise as potential molecular targets for therapeutic interventions aimed at managing hypertrophic scars.

Diagnosis and treatment of diabetic foot ulcer complicated with lower extremity vasculopathy: Consensus recommendation from the Chinese Medical Association (CMA), Chinese Medical Doctor Association (CMDA).

Diabetic foot ulcer complicated with lower extremity vasculopathy is highly prevalent, slow healing and have a poor prognosis. The final progression leads to amputation, or may even be life-threatening, seriously affecting patients' quality of life. The treatment of lower extremity vasculopathy is the focus of clinical practice and is vital to improving the healing process of diabetic foot ulcers. Recently, a number of clinical trials on diabetic foot ulcers with lower extremity vasculopathy have been reported. A joint group of Chinese Medical Association (CMA) and Chinese Medical Doctor Association (CMDA) expert representatives reviewed and reached a consensus on the guidelines for the clinical diagnosis and treatment of this kind of disease. These guidelines are based on evidence from the literature and cover the pathogenesis of diabetic foot ulcers complicated with lower extremity vasculopathy and the application of new treatment approaches. These guidelines have been put forward to guide practitioners on the best approaches for screening, diagnosing and treating diabetic foot ulcers with lower extremity vasculopathy, with the aim of providing optimal, evidence-based management for medical personnel working with diabetic foot wound repair and treatment.

An evaluation of nursing students' learning self-efficacy: A multi-dimensional instrument development and structural validation.

BACKGROUND: Nursing learning self-efficacy (NLSE) is essential in nursing students' learning, and since it is a task-dependent construct, accurate measurements require a multidimensional instrument. OBJECTIVE: This research aimed to develop and validate a multidimensional NLSE instrument to measure Taiwanese nursing students' views of nursing learning self-efficacy. DESIGN: The cross-sectional study design was used for this investigation. PARTICIPANTS: The study included 1143 nursing students from a nursing junior college. METHODS: To assess the validity and reliability of the instrument's factors, exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were utilized. Conceptual understanding, higher-order cognitive skills, practical work, everyday application, and nursing communication were identified as five factors. A comparison of five proposed models was also conducted. RESULTS: The study found that the correlated and one-factor second-order models were acceptable and provided a simple structure for evaluating nursing students' perceptions of NLSE. Furthermore, a specific model with two second-order scales (Cognition and Application) and one first-order scale (nursing communication) was identified, highlighting the crucial role of nursing communication in nursing students' self-efficacy. CONCLUSIONS: Evaluating nursing students' learning self-efficacy using a valid and reliable instrument is crucial for understanding their learning confidence. The creation of such a scale constitutes the primary contribution of this study.

Extracellular vesicles from 3D cultured dermal papilla cells improve wound healing via Krüppel-like factor 4/vascular endothelial growth factor A -driven angiogenesis.

Background: Non-healing wounds are an intractable problem of major clinical relevance. Evidence has shown that dermal papilla cells (DPCs) may regulate the wound-healing process by secreting extracellular vesicles (EVs). However, low isolation efficiency and restricted cell viability hinder the applications of DPC-EVs in wound healing. In this study, we aimed to develop novel 3D-DPC spheroids (tdDPCs) based on self-feeder 3D culture and to evaluate the roles of tdDPC-EVs in stimulating angiogenesis and skin wound healing. Methods: To address the current limitations of DPC-EVs, we previously developed a self-feeder 3D culture method to construct tdDPCs. DPCs and tdDPCs were identified using immunofluorescence staining and flow cytometry. Subsequently, we extracted EVs from the cells and compared the effects of DPC-EVs and tdDPC-EVs on human umbilical vein endothelial cells (HUVECs) in vitro using immunofluorescence staining, a scratch-wound assay and a Transwell assay. We simultaneously established a murine model of full-thickness skin injury and evaluated the effects of DPC-EVs and tdDPC-EVs on wound-healing efficiency in vivo using laser Doppler, as well as hematoxylin and eosin, Masson, CD31 and α-SMA staining. To elucidate the underlying mechanism, we conducted RNA sequencing (RNA-seq) of tdDPC-EV- and phosphate-buffered saline-treated HUVECs. To validate the RNA-seq data, we constructed knockdown and overexpression vectors of Krüppel-like factor 4 (KLF4). Western blotting, a scratch-wound assay, a Transwell assay and a tubule-formation test were performed to detect the protein expression, cell migration and lumen-formation ability of KLF4 and vascular endothelial growth factor A (VEGFA) in HUVECs incubated with tdDPC-EVs after KLF4 knockdown or overexpression. Dual-luciferase reporter gene assays were conducted to verify the activation effect of KLF4 on VEGFA. Results: We successfully cultured tdDPCs and extracted EVs from DPCs and tdDPCs. The tdDPC-EVs significantly promoted the proliferation, lumen formation and migration of HUVECs. Unlike DPC-EVs, tdDPC-EVs exhibited significant advantages in terms of promoting angiogenesis, accelerating wound healing and enhancing wound-healing efficiency both in vitro and in vivo. Bioinformatics analysis and further functional experiments verified that the tdDPC-EV-regulated KLF4/VEGFA axis is pivotal in accelerating wound healing. Conclusions: 3D cultivation can be utilized as an innovative optimization strategy to effectively develop DPC-derived EVs for the treatment of skin wounds. tdDPC-EVs significantly enhance wound healing via KLF4/VEGFA-driven angiogenesis.

Adipose Mesenchymal Stem Cell Derived Exosomes Promote Keratinocytes and Fibroblasts Embedded in Collagen/Platelet-Rich Plasma Scaffold and Accelerate Wound Healing.

Engineered skin substitutes derived from human skin significantly reduce inflammatory reactions mediated by foreign/artificial materials and are consequently easier to use for clinical application. Type I collagen is a main component of the extracellular matrix during wound healing and has excellent biocompatibility, and platelet-rich plasma can be used as the initiator of the healing cascade. Adipose mesenchymal stem cell derived exosomes are crucial for tissue repair and play key roles in enhancing cell regeneration, promoting angiogenesis, regulating inflammation, and remodeling extracellular matrix. Herein, Type I collagen and platelet-rich plasma, which provide natural supports for keratinocyte and fibroblast adhesion, migration, and proliferation, are mixed to form a stable 3D scaffold. Adipose mesenchymal stem cell derived exosomes are added to the scaffold to improve the performance of the engineered skin. The physicochemical properties of this cellular scaffold are analyzed, and the repair effect is evaluated in a full-thickness skin defect mouse model. The cellular scaffold reduces the level of inflammation and promotes cell proliferation and angiogenesis to accelerate wound healing. Proteomic analysis shows that exosomes exhibit excellent anti-inflammatory and proangiogenic effects in collagen/platelet-rich plasma scaffolds. The proposed method provides a new therapeutic strategy and theoretical basis for tissue regeneration and wound repair.

Activation of Sestrin2 accelerates deep second-degree burn wound healing through PI3K/AKT pathway.

Deep second-degree burns heal slowly, and promoting the healing process is a focus of clinical research. Sestrin2 is a stress-inducible protein with antioxidant and metabolic regulatory effects. However, its role during acute dermal and epidermal re-epithelialization in deep second-degree burns is unknown. In this study, we aimed to explore the role and molecular mechanism of sestrin2 in deep second-degree burns as a potential treatment target for burn wounds. To explore the effects of sestrin2 on burn wound healing, we established a deep second-degree burn mouse model. Then we detected the expression of sestrin2 by western blot and immunohistochemistry after obtaining the wound margin of full-thickness burned skin. The effects of sestrin2 on burn wound healing were explored in vivo and in vitro through interfering sestrin2 expression using siRNAs or the small molecule agonist of sestrin2, eupatilin. We also investigated the molecular mechanism of sestrin2 in promoting burn wound healing by western blot and CCK-8 assay. Our in vivo and in vitro deep second-degree burn wound healing model demonstrated that sestrin2 was promptly induced at murine skin wound edges. The small molecule agonist of sestrin2 accelerated the proliferation and migration of keratinocytes, as well as burn wound healing. Conversely, the healing of burn wounds was delayed in sestrin2-deficient mice and was accompanied by the secretion of inflammatory cytokines as well as the suppression of keratinocyte proliferation and migration. Mechanistically, sestrin2 promoted the phosphorylation of the PI3K/AKT pathway, and inhibition of PI3K/AKT pathway abrogated the promoting role of sestrin2 in keratinocyte proliferation and migration. Therefore, sestrin2 plays a critical role in activation of the PI3K/AKT pathway to promote keratinocyte proliferation and migration, as well as re-epithelialization in the process of deep second-degree burn wound repair.

The deacetylation of Akt by SIRT1 inhibits inflammation in macrophages and protects against sepsis.

Sepsis is characterized by uncontrolled inflammatory response and altered polarization of macrophages at the early phase. Akt is known to drive macrophage inflammatory response. However, how macrophage inflammatory response is fine-tuned by Akt is poorly understood. Here, we found that Lys14 and Lys20 of Akt is deacetylated by the histone deacetylase SIRT1 during macrophage activation to suppress macrophages inflammatory response. Mechanistically, SIRT1 promotes Akt deacetylation to inhibit the activation of NF-κB and pro-inflammatory cytokines. Loss of SIRT1 facilitates Akt acetylation and thus promotes inflammatory cytokines in mouse macrophages, potentially worsen the progression of sepsis in mice. By contrast, the upregulation of SIRT1 in macrophages further contributes to the inhibition of pro-inflammatory cytokines via Akt activation in sepsis. Taken together, our findings establish Akt deacetylation as an essential negative regulatory mechanism that curtails M1 polarization.

Efficiency and Mechanism Evaluation of Magnolia officinalis Water Extract in Preventing Gastric Ulcer.

In this study we aimed at demonstrating the ability of Magnolia officinalis water extract to ameliorate gastric ulcers in in vitro and in vivo experiments. The gastric mucosa epithelial cell line, RGM 1, was pretreated with Magnolia officinalis water extract (0, 0.1, 1, 2, 5, or 10 mg/ml) and cultured in DMEM/F12 medium (pH 7.4) for 2 h and then in DMEM/F12 medium (pH 4.0) for 10 min. Magnolia officinalis water extract protected the cell viability and decreased reactive oxygen species formation by the acidic medium. In the in vivo experiment, Magnolia officinalis water extract (100 mg/kg) was administrated daily for 28 days in ICR mice via oral gavage, and then Shay's ulcer surgical method was performed to induce gastric ulcers. We analyzed the pH value of stomach acid and the pathological section, inflammation, and cannabinoid receptor type 2 (CB2) cDNA levels of the stomach. Magnolia officinalis water extract not only enhanced the pH value of stomach acid but also ameliorated the ulcer index and inflammation and increased CB2 expression effectively. These results suggest that Magnolia officinalis water extract might be used to decrease the incidence of gastric ulcer.

Exosome/metformin-loaded self-healing conductive hydrogel rescues microvascular dysfunction and promotes chronic diabetic wound healing by inhibiting mitochondrial fission.

Chronic diabetic wounds remain a globally recognized clinical challenge. They occur due to high concentrations of reactive oxygen species and vascular function disorders. A promising strategy for diabetic wound healing is the delivery of exosomes, comprising bioactive dressings. Metformin activates the vascular endothelial growth factor pathway, thereby improving angiogenesis in hyperglycemic states. However, multifunctional hydrogels loaded with drugs and bioactive substances synergistically promote wound repair has been rarely reported, and the mechanism of their combinatorial effect of exosome and metformin in wound healing remains unclear. Here, we engineered dual-loaded hydrogels possessing tissue adhesive, antioxidant, self-healing and electrical conductivity properties, wherein 4-armed SH-PEG cross-links with Ag+, which minimizes damage to the loaded goods and investigated their mechanism of promotion effect for wound repair. Multiwalled carbon nanotubes exhibiting good conductivity were also incorporated into the hydrogels to generate hydrogen bonds with the thiol group, creating a stable three-dimensional structure for exosome and metformin loading. The diabetic wound model of the present study suggests that the PEG/Ag/CNT-M + E hydrogel promotes wound healing by triggering cell proliferation and angiogenesis and relieving peritraumatic inflammation and vascular injury. The mechanism of the dual-loaded hydrogel involves reducing the level of reactive oxygen species by interfering with mitochondrial fission, thereby protecting F-actin homeostasis and alleviating microvascular dysfunction. Hence, we propose a drug-bioactive substance combination therapy and provide a potential mechanism for developing vascular function-associated strategies for treating chronic diabetic wounds.

Extracellular vesicles from Lactobacillus druckerii inhibit hypertrophic scar fibrosis.

BACKGROUND: Hypertrophic scars (HS) affect millions of people each year and require better treatment strategies. Bacterial extracellular vesicles (EVs) are advantaged by low cost and high yield which was commonly used in the treatment of diseases. Here, we investigated the therapeutic efficacy of EVs obtained from Lactobacillus druckerii in hypertrophic scar. In vitro, the effects of Lactobacillus druckerii-derived EVs (LDEVs) on Collagen I/III and α-SMA in fibroblasts obtained from HS. In vivo, a scleroderma mouse model was used to investigate the effects of LDEVs on fibrosis. The impact of LDEVs on excisional wound healing was explored. The different proteins between PBS and LDEVs treated fibroblasts derived from hypertrophic scar were studied by untargeted proteomic analysis. RESULTS: In vitro, LDEVs treatment significantly inhibited the expression of Collagen I/III and α-SMA and cell proliferation of fibroblasts derived from HS. In vivo, LDEVs withdrawn the hypertrophic scar formation in scleroderma mouse model and decreased the expression of α-SMA. LDEVs promoted the proliferation of skin cells, new blood vessel formation and wound healing in excisional wound healing mice model. Moreover, proteomics has shown that LDEVs inhibit hypertrophic scar fibrosis through multiple pathways. CONCLUSIONS: Our results indicated that Lactobacillus druckerii-derived EVs has the potential application in the treatment of hypertrophic scars and any other fibrosis diseases.

miR-125b-5p in adipose derived stem cells exosome alleviates pulmonary microvascular endothelial cells ferroptosis via Keap1/Nrf2/GPX4 in sepsis lung injury.

BACKGROUND: Sepsis is a fatal disease with a high rate of morbidity and mortality, during which acute lung injury is the earliest and most serious complication. Injury of pulmonary microvascular endothelial cells (PMVECs) induced by excessive inflammation plays an important role in sepsis acute lung injury. This study is meant to explore the protective effect and mechanism of ADSCs exosomes on excessive inflammation PMVECs injury. RESULTS: We successfully isolated ADSCs exosomes, the characteristic of which were confirmed. ADSCs exosomes reduced excessive inflammatory response induced ROS accumulation and cell injury in PMVECs. Besides, ADSCs exosomes inhibited excessive inflammatory response induced ferroptosis while upregulated expression of GPX4 in PMVECs. And further GPX4 inhibition experiments revealed that ADSCs exosomes alleviated inflammatory response induced ferroptosis via upregulating GPX4. Meanwhile, ADSCs exosomes could increase the expression and nucleus translocation of Nrf2, while decrease the expression of Keap1. miRNA analysis and further inhibition experiments verified that specific delivery of miR-125b-5p by ADSCs exosomes inhibited Keap1 and alleviated ferroptosis. In CLP induced sepsis model, ADSCs exosomes could relieve the lung tissue injury and reduced the death rate. Besides, ADSCs exosomes alleviated oxidative stress injury and ferroptosis of lung tissue, while remarkably increase expression of Nrf2 and GPX4. CONCLUSION: Collectively, we illustrated a novel potentially therapeutic mechanism that miR-125b-5p in ADSCs exosomes could alleviate the inflammation induced PMVECs ferroptosis in sepsis induced acute lung injury via regulating Keap1/Nrf2/GPX4 expression, hence improve the acute lung injury in sepsis.

[Expression of Key Enzymes in Glucose Metabolism in Chronic Mountain Sickness and Its Correlation with Phenotype].

OBJECTIVE: To explore the pathogenesis of erythrocytosis by detecting the key enzymes of glucose metabolism and glucose transporter in bone marrow erythrocytes of chronic mountain sickness (CMS), and analyzing its correlation with hemoglobin. METHODS: Twenty CMS patients hospitalized in Qinghai Provincial People's Hospital from January 2019 to December 2020 were selected as CMS group. Twenty males with leukocyte count > 3.5×109/L who had accepted bone marrow aspiration and had normal result were taken as control group. The mRNA and protein expression of key enzymes and glucose transporter in glucose metabolism in bone marrow CD71+ erythrocytes were detected by real time qPCR and Western blot, respectively. Glucose, lactic acid and 2,3-diphosphoglycerate in the bone marrow supernatant and serum were tested by ELISA. The mRNA and protein expression of key enzymes and glucose transporter, glucose, lactic acid and 2,3-diphosphoglycerate of the two groups were compared. Pearson correlation was used to analyze the correlation between key enzymes, glucose transporter in glucose metabolism in bone marrow CD71+ erythrocytes and hemoglobin. RESULTS: The expression of HK2, GLUT1 and GLUT2 mRNA in the CMS group were higher than those in the control group (P<0.001), while the expression of HK1, OGDH and COX5B mRNA were not different. The expression of HK2, GLUT1 and GLUT2 protein in the CMS group were higher than those in the control group (P<0.05). The levels of glucose and lactic acid in the bone marrow supernatant and serum in the CMS group were not different from those in the control group, while the level of 2,3-diphosphoglycerate was higher (P<0.001). Both HK2 and GLUT2 proteins were positively correlated with hemoglobin (r=0.511, 0.717). CONCLUSION: CMS patients may increase glycolysis by increasing the expression of HK2, and promote the utilization of glucose through high expression of GLUT1 and GLUT2 to meet the need of energy supply.

Efficiency comparison of an isoeugenol-derivated compound, eugenosedin-A, with glibenclamide and pioglitazone in protecting cardiovascular dysfunction of diabetic SHR.

This study was to investigate three agents possible protective effect against DM-induced cardiovascular dysfunction in spontaneously hypertensive rats (SHR). Control group was fed normal diet, DM group was injected with STZ/NA and fed high fat diet (HFD), and treatment groups were given STZ/NA, fed HFD, and then oral gavaged with eugenosedin-A (Eu-A), glibenclamide (Gli), or pioglitazone (Pio) 5 mg/kg/per day for 4-week, respectively. Eu-A, Gli, and Pio clearly ameliorated the changes of body weight, cardiac weight, and the biochemical parameters, cardiovascular disorders and inflammation. Like Gli and Pio, Eu-A may be effectively to control DM and the cardiovascular dysfunction.

Deacetylation of IRF8 inhibits iNOS expression and inflammation via SIRT1 in macrophages.

AIMS: Dysregulated interferon regulatory factor 8 (IRF8) mediated inducible nitric oxide synthase (iNOS) transcription is crucial to the pathogenesis of several inflammatory disorders. However, the molecular mechanism that control the transcription activity of IRF8 in the regulation of iNOS is not fully elucidated. This study is undertaken to determine whether SIRT1 impacts IRF8 acetylation level in the macrophages. MAIN METHODS: The silver stain, mass spectrum, bone marrow-derived monocytes differentiation, lentiviral transduction, immunoprecipitation and chromatin immunoprecipitation assay were used to investigate the relationship between IRF8 and SIRT1. KEY FINDINGS: We demonstrate that deacetylation of IRF8 is induced by lipopolysaccharide (LPS) and suppresses iNOS expression. Macrophages expressing acetylation-defective iNOS are highly septic upon transfer to macrophages cleaned up mice. Mechanistically, deacetylation IRF8 facilitates the binding of silent information regulator 1 (SIRT1) to the iNOS promoter and restricts iNOS transcription. The expression of iNOS was enhanced in the macrophages from SIRT1 conditional knockout mice and the progression of sepsis is more serious. SIGNIFICANCE: The discovery of the IRF8-SIRT1 interaction that governs iNOS expression may exploit new therapeutic strategies for inflammatory disorders.

Adiponectin ameliorates hypertrophic scar by inhibiting Yes-associated protein transcription through SIRT1-mediated deacetylation of C/EBPß and histone H3.

The clinical correlation between adiponectin (APN) signal and hypertrophic scar (HS) remains unclear. Here, we found significantly reduced expression of APN receptors (AdipoR1/2) in HS tissues and derived fibroblasts (HFs), suggesting that HS formation may be associated with APN/AdipoR1/2 decline. RNA sequencing and RT-PCR validation revealed that APN significantly elevated the expression of SIRT1. Both in vitro and in vivo experiments confirmed that SIRT1 plays important role in APN inhibiting the fibrotic phenotype transformation and proliferation of scar fibroblasts and improving skin fibrosis. Mechanistically, SIRT1 inhibited the acetylation of C/EBPß K39, histone H3K27, and H3K9, resulting in impaired transcription activity of C/EBPß and compact chromatin conformation, thus preventing C/EBPß from activating the transcription of YAP. Moreover, we found that YAP was critical for the transcriptional regulation of CTGF, CCND1, and CCNE1 by TEAD4. In conclusion, our study revealed the role of APN in antagonizing HS fibrosis by regulating the SIRT1/C/EBPß/YAP pathway.

Exosomes Derived from Adipose Mesenchymal Stem Cells Promote Diabetic Chronic Wound Healing through SIRT3/SOD2.

Chronic wounds resulting from diabetes are a major health concern in both industrialized and developing countries, representing one of the leading causes of disability and death. This study aimed to investigate the effect of adipose mesenchymal stem cell-derived exosomes (ADSC-exos) on diabetic wounds and the mechanism underlying this effect. The results showed that ADSC-exos could improve oxidative stress and secretion of inflammatory cytokines in diabetic wounds, thereby increasing periwound vascularization and accelerating wound healing. At the cellular level, ADSC-exos reduced reactive oxygen species (ROS) generation in human umbilical vein endothelial cells (HUVECs) and improved mitochondrial function in a high-glucose environment. Moreover, the Western blot analysis showed that the high-glucose environment decreased Sirtuin 3 (SIRT3) expression, while exosome treatment increased SIRT3 expression. The activity of superoxide dismutase 2 (SOD2) was enhanced, and the level of inflammatory cytokines was decreased. Further, SIRT3 interference experiments indicated that the effects of ADSC-exos on oxidative stress and angiogenesis were partly dependent on SIRT3. After SIRT3 was inhibited, ROS production increased, while mitochondrial membrane potential and SOD2 activity decreased. These findings confirmed that ADSC-exos could improve the level of high-glucose-induced oxidative stress, promote angiogenesis, and reduce mitochondrial functional impairment and the inflammatory response by regulating SIRT3/SOD2, thus promoting diabetic wound healing.

Functionalizing multi-component bioink with platelet-rich plasma for customized in-situ bilayer bioprinting for wound healing.

In-situ three-dimensional (3D) bioprinting has been emerging as a promising technology designed to rapidly seal cutaneous defects according to their contour. Improvements in the formulations of multi-component bioink are needed to support cytocompatible encapsulation and biological functions. Platelet-rich plasma (PRP), as a source of patient-specific autologous growth factors, exhibits capabilities in tissue repair and rejuvenation. This study aimed to prepare PRP-integrated alginate-gelatin (AG) composite hydrogel bioinks and evaluate the biological effects in vitro and in vivo. 3D bioprinted constructs embedded with dermal fibroblasts and epidermal stem cells were fabricated using extrusion strategy. The integration of PRP not only improved the cellular behavior of seeded cells, but regulate the tube formation of vascular endothelial cells and macrophage polarization in a paracrine manner, which obtained an optimal effect at an incorporation concentration of 5%. For in-situ bioprinting, PRP integration accelerated the high-quality wound closure, modulated the inflammation and initiated the angiogenesis compared with the AG bioink. In conclusion, we revealed the regenerative potential of PRP, readily available at the bedside, as an initial signaling provider in multi-component bioink development. Combined with in-situ printing technology, it is expected to accelerate the clinical translation of rapid individualized wound repair.

Pre-germinated brown rice alleviates non-alcoholic fatty liver disease induced by high fructose and high fat intake in rat.

In past researches, we had been proved the action mechanism of pre-germinated brown rice (PGBR) to treat metabolic syndrome and diabetes mellitus. This study was to investigate the protective effect of PGBR in high fructose and high fat-induced non-alcoholic fatty liver disease (NAFLD) in rodents. WKY rats were divided into: Control group was fed normal drinking water and diet; FLD group was fed 10% high-fructose-water (HFW) and high-fat-diet (HFD); PGBR group was given HFW, and HFD mixed PGBR. After four weeks, the body, hepatic and cardiac weight gains of FLD group had significant increases than that of Control group. The enhanced blood pressure and heart rate, hypertriglyceridemia, hyperuricemia, and higher liver function index (GPT levels) were observed; meanwhile, the IL-6 and TNF-α levels of serum, and TG level of liver were also elevated in FLD group. The related protein expressions of lipid synthesis, inflammation, cardiac fibrosis, and hypertrophy were deteriorated by HFW/HFD. However, in treatment group, PGBR decreased all above influenced parameters, additionally GOT; and related protein expressions. PGBR treated HFW/HFD-induced NAFLD and cardiac complications might be via improving lipid homeostasis, and inhibiting inflammation. Together, PGBR could be used as a healthy food for controlling NAFLD and its' cardiac dysfunction.

KLF4 Alleviates Hypertrophic Scar Fibrosis by Directly Activating BMP4 Transcription.

Background: Hypertrophic scars (HS) often occur after burns, surgery and extensive trauma. Krüppel-like factor 4 (KLF4) is a member of the Krüppel-like factor family, a group of conserved zinc finger transcription factors that regulate diverse cellular processes. KLF4 can participate in the regulation of fibrotic diseases in many organs, such as the lung, liver, and heart. However, the antifibrotic effect of KLF4 in skin HS remains elusive. Result: This study observed the inhibition of KLF4 on fibrosis in vivo and in vitro. Our results revealed that KLF4 expression was decreased in HS tissue and fibroblasts. The results of KLF4 transfection confirmed its ability to alleviate the transdifferentiation of fibroblasts into myofibroblasts both in vitro and in vivo, thereby inhibiting the development of fibrosis. In addition, ChIP assays showed that BMP4 was the target gene of KLF4 for inhibiting skin fibrosis. Conclusions: Collectively, this evidence indicates that KLF4 is associated with BMP4 and could play an important regulatory role in HS formation by downregulating myofibroblast transdifferentiation. Our study provides a new target for the prevention and treatment of hypertrophic scars.